Psychometric properties of the New General Self-Efficacy Scale for Vietnamese persons with colorectal cancer.

Background: There are currently no specific tools available to assess self-efficacy among Vietnamese individuals with colorectal cancer (CRC) post-surgery. Translating and evaluating the psychometric properties of the New General Self-Efficacy Scale (NGSE) for use in the Vietnamese population could help address this gap. Objective: This study aimed to evaluate the psychometric properties of the Vietnamese version of the NGSE scale. Methods: A cross-sectional study was conducted. The sample consisted of 120 individuals aged 20-59 with CRC post-surgery, recruited through a multi-stage sampling technique from three hospitals in Vietnam. The scale was translated into Vietnamese using Brislin's technique. Content validity was assessed using the Content Validity Index for item (I-CVI) and for scale (S-CVI). Construct validity was examined through confirmatory factor analysis (CFA), and reliability was measured using Cronbach's α coefficients. Results: The findings showed an I-CVI of 1.00 and an S-CVI of 1.00, indicating excellent content validity. The Cronbach's α for the NGSE was 0.95, indicating excellent internal consistency. CFA results showed that all eight items fit well within a unidimensional structure (χ2 = 48.936, p >0.05, df = 24, χ2/df = 2.04, RMSEA = 0.078, CFI = 0.979, TLI = 0.971, SRMR = 0.023). Factor loadings for each item ranged from 0.798 to 0.901. Conclusion: The results suggest that the NGSE scale demonstrates good psychometric properties as applied to the Vietnamese individuals examined in this study. This instrument can be regularly utilized in clinical settings to identify key concerns in colorectal cancer patients' care and facilitate appropriate nursing interventions to enhance self-efficacy in this population effectively.

A causal model of health-related quality of life in colorectal cancer patients post-surgery.

PURPOSE: this study aims to develop and test a model examining the causal relationship between self-efficacy, social support, fatigue, pain, functional status, and health-related quality of life (HRQL). METHODS: A cross-sectional correlation study was conducted using a multi-stage sampling technique to recruit 256 individuals aged 20 to 59 with colorectal cancer (CRC) post-surgery from three hospitals in Northern Vietnam. The hypothesized model, based on Ferrans' HRQL conceptual model and literature review, was validated using structural equation modeling (SEM) and Mplus. RESULTS: the model fit the data well, explaining 52% of the variance of HRQL. Self-efficacy emerged as the most influential factor directly impacting HRQL (ß = .494, p < .05) and also had negative indirect effects on HRQL through fatigue and pain (ß = -.271, p < .05). Social support had a positive direct (ß = .406, p < .001) and negative indirect effects on HRQL via fatigue and pain (ß = -.143, p < .05). Fatigue and pain had negative indirect effects on HRQL through functional status (ß = -.336, p < .05 and ß = -.219, p < .05, respectively). Functional status had a positive direct effect on HRQL (ß = .418, p < .001). CONCLUSIONS: The study's findings highlight the importance of improving self-efficacy, social support, and functional status, while reducing fatigue and pain to enhance HRQL among individuals with CRCpost-surgery. These insights can inform the development of targeted interventions to improve the well-being of this population.

Translation and Validation of a Vietnamese Version of the Colorectal Cancer Subscale for the Functional Assessment of Cancer Therapy - Colorectal Questionnaire.

Introduction: There is a need for a validated Vietnamese translation of the colorectal cancer subscale (CCS) of the functional assessment of cancer therapy-colorectal (FACT-C) questionnaire to assess colorectal cancer-specific concerns of Vietnamese persons with colorectal cancer post-surgery. Objectives: This study aims to translate and validate the CCS of FACT-C questionnaire in Vietnamese persons with colorectal cancer post-surgery. Methods: The nine-item CCS was translated following the functional assessment of chronic illness therapy (FACIT) translation methodology guidelines. Psychometric properties of a Vietnamese version of the CCS were evaluated with a sample of 135 participants who were randomly selected from three hospitals in Vietnam, utilizing a multistage sampling method. Construct validity was examined through confirmatory factor analysis (CFA), and reliability was assessed using Cronbach's α coefficients. These measures aimed to validate the psychometric properties of the Vietnamese nine-item CCS version. Descriptive statistics were used to analyze participant demographics with SPSS. Results: The translated version demonstrated equivalence to the original English version. CFA results for the CCS Vietnamese version indicated that all 9 items were consistent with a unidimensional questionnaire (χ2 = 69.669, p > .05, df = 27, χ2/df = 2.58, RMSEA = .074, CFI = .917, TLI = .901, SRMR = .057). The Cronbach's α coefficient was .86, indicating high reliability. The Correlated Item-Total Correlation for the 9 items ranged from .39 to .76. Conclusion: The nine-item CCS Vietnamese version demonstrated appropriate translation, establishing its validity and reliability in measuring colorectal cancer-related concerns within the health-related quality of life among Vietnamese persons post-surgery.

Corrigendum: Effectiveness of perindopril/amlodipine fixed-dose combination in the treatment of hypertension: a systematic review.

[This corrects the article DOI: 10.3389/fphar.2023.1156655.].

Glycoside constituents from Cayratia geniculata.

Using various chromatographic separations, six glycoside derivatives (1-6), including one new ent-labdane glucoside named cayratioside (1), were isolated from the methanol extract of Cayratia geniculata stems and leaves. Their structures were elucidated by detailed analysis of the 1D, 2D NMR, and HRESIQTOF mass spectra. The inhibitory effect of 1-6 on LPS-induced NO production in RAW264.7 cells was also evaluated. Among isolated compounds, 1 exhibited moderate activity with an IC50 value of 59.65 ± 1.85 µM.

Caffeoylquinic acid esters, lignans and flavones from Yua thomsonii with cytotoxic and nitric oxide inhibitory activities.

Phytochemical study on the aerial parts of Yua thomsonii resulted in the isolation of 11 secondary metabolites, including a new caffeoyl quinic acid derivative, 3-O-trans-caffeoyl-4-O-acetylquinic acid methyl ester (1), a new dihydrobenzofuran neolignan, 3,5-dimethoxy-4-(1″,3″-dihydroxy-2″-propyloxyl)-4',7-epoxy-8,5'-neolignan-4,9,9'-triol (3) and nine known compounds, methyl 4-O-coumaroylquinate (2), (7S*,8S*)-3-methoxy-3',7-epoxy-8,4'-oxyneolignan-4,9,9'-triol (4), kompasinol A (5), lyoniresinol (6), schizandriside (7), (-)-isolariciresinol 3a-O-ß-D-xylopyranoside (8), lyoniside (9), vitexin (10) and luteolin 4'-O-ß-glucopyranoside (11). Their structures were elucidated using comprehensive spectroscopic methods, including 1D and 2D NMR and HRESI mass spectra. The absolute configurations of 1 and 3 were deduced by electronic circular dichroism spectroscopy. Compounds 1, 3, 5 and 6 exhibited nitric oxide (NO) inhibitory effects, with IC50 values ranging from 12.18 to 29.45 µM. However, compounds 1, 3, 6 and 8 were non-cytotoxic towards HepG2 and MCF-7 carcinoma cells.

The impact of antibiotics on the gut microbiota of children recovering from watery diarrhoea.

Infectious diarrhoeal diseases remain a substantial health burden in young children in low- and middle-income countries. The disease and its variable treatment options significantly alter the gut microbiome, which may affect clinical outcomes and overall gut health. Antibiotics are often prescribed, but their impact on the gut microbiome during recovery is unclear. Here, we used 16S rRNA sequencing to investigate changes in the gut microbiota in Vietnamese children with acute watery diarrhoea, and highlight the impact of antibiotic treatment on these changes. Our analyses identified that, regardless of treatment, recovery was characterised by reductions in Streptococcus and Rothia species and expansion of Bacteroides/Phocaeicola, Lachnospiraceae and Ruminococcacae taxa. Antibiotic treatment significantly delayed the temporal increases in alpha- and beta-diversity within patients, resulting in distinctive patterns of taxonomic change. These changes included a pronounced, transient overabundance of Enterococcus species and depletion of Bifidobacterium pseudocatenulatum. Our findings demonstrate that antibiotic treatment slows gut microbiota recovery in children following watery diarrhoea.

Soluble Frizzled-related proteins promote exosome-mediated Wnt re-secretion.

Wnt proteins are thought to be transported in several ways in the extracellular space. For instance, they are known to be carried by exosomes and by Wnt-carrier proteins, such as sFRP proteins. However, little is known about whether and/or how these two transport systems are related. Here, we show that adding sFRP1 or sFRP2, but not sFRP3 or sFRP4, to culture medium containing Wnt3a or Wnt5a increases re-secretion of exosome-loaded Wnt proteins from cells. This effect of sFRP2 is counteracted by heparinase, which removes sugar chains on heparan sulfate proteoglycans (HSPGs), but is independent of LRP5/6, Wnt co-receptors essential for Wnt signaling. Wnt3a and Wnt5a specifically dimerize with sFRP2 in culture supernatant. Furthermore, a Wnt3a mutant defective in heterodimerization with sFRP2 impairs the ability to increase exosome-mediated Wnt3a re-secretion. Based on these results, we propose that Wnt heterodimerization with its carrier protein, sFRP2, enhances Wnt accumulation at sugar chains on HSPGs on the cell surface, leading to increased endocytosis and exosome-mediated Wnt re-secretion. Our results suggest that the range of action of Wnt ligands is controlled by coordination of different transport systems.

Targeted sequencing from cerebrospinal fluid for rapid identification of drug-resistant tuberculous meningitis.

Mortality from tuberculous meningitis (TBM) remains around 30%, with most deaths occurring within 2 months of starting treatment. Mortality from drug-resistant strains is higher still, making early detection of drug resistance (DR) essential. Targeted next-generation sequencing (tNGS) produces high read depths, allowing the detection of DR-associated alleles with low frequencies. We applied Deeplex Myc-TB-a tNGS assay-to cerebrospinal fluid (CSF) samples from 72 adults with microbiologically confirmed TBM and compared its genomic drug susceptibility predictions to a composite reference standard of phenotypic susceptibility testing (pDST) and whole genome sequencing, as well as to clinical outcomes. Deeplex detected Mycobacterium tuberculosis complex DNA in 24/72 (33.3%) CSF samples and generated full DR reports for 22/24 (91.7%). The read depth generated by Deeplex correlated with semi-quantitative results from MTB/RIF Xpert. Alleles with <20% frequency were seen at canonical loci associated with first-line DR. Disregarding these low-frequency alleles, Deeplex had 100% concordance with the composite reference standard for all drugs except pyrazinamide and streptomycin. Three patients had positive CSF cultures after 30 days of treatment; reference tests and Deeplex identified isoniazid resistance in two, and Deeplex alone identified low-frequency rifampin resistance alleles in one. Five patients died, of whom one had pDST-identified pyrazinamide resistance. tNGS on CSF can rapidly and accurately detect drug-resistant TBM, but its application is limited to those with higher bacterial loads. In those with lower bacterial burdens, alternative approaches need to be developed for both diagnosis and resistance detection.

Evaluation of the impact before and after the application of an antimicrobial stewardship program at Dong Thap General Hospital, Vietnam, from 2017 to 2021.

Background: Vietnam has one of the highest rates of antibiotic resistance in Asia. In 2020, the Vietnam Minister of Health introduced new legislation for the implementation of an antimicrobial stewardship program (ASP). The evidence for the effectiveness of ASP in small hospitals and hospitals located in provinces was limited compared with larger-scale and central city hospitals. Aim: Evaluation of the impact before and after the introduction of an antimicrobial stewardship program at Dong Thap General Hospital, from 2017 to 2021. Methods: Retrospective data was collected from June 2017 to June 2021. The impact of the ASP on changes in antibiotic use and the clinical outcome associated with the implementation of the ASP was evaluated using autoregressive integrated moving average modelling of controlled interrupted time-series analysis. Results: There was a significant and sustained decrease in antibiotic consumption level (step change) in 2 indicators, DOT/1000PD (129.55; P<0.01) and LOT/1000PD (99.95, P<0.01), immediately after the ASP intervention. There were no statistically significant changes identified in terms of consumption with DDD/1000PD, or in the clinical outcomes. The results showed no statistically significant change in consumption trend (ramps) in all evaluated indicators. No statistically significant changes in consumption levels and trends were observed in the control group. Conclusion: The ASP implemented in Dong Thap General Hospital from 2017 to 2021 showed a considerable influence on antibiotic consumption as indicated by the DOT/1000 PD and LOT/1000 PD during the initial stages. Moreover, controlling antibiotic consumption did not negatively impact patient outcomes.

Multidrug resistance plasmids underlie clonal expansions and international spread of Salmonella enterica serotype 1,4,[5],12:i:- ST34 in Southeast Asia.

Salmonella enterica serotype 1,4,[5],12:i:- (Typhimurium monophasic variant) of sequence type (ST) 34 has emerged as the predominant pandemic genotype in recent decades. Despite increasing reports of resistance to antimicrobials in Southeast Asia, Salmonella ST34 population structure and evolution remained understudied in the region. Here we performed detailed genomic investigations on 454 ST34 genomes collected from Vietnam and diverse geographical sources to elucidate the pathogen's epidemiology, evolution and antimicrobial resistance. We showed that ST34 has been introduced into Vietnam in at least nine occasions since 2000, forming five co-circulating major clones responsible for paediatric diarrhoea and bloodstream infection. Most expansion events were associated with acquisitions of large multidrug resistance plasmids of IncHI2 or IncA/C2. Particularly, the self-conjugative IncA/C2 pST34VN2 (co-transferring blaCTX-M-55, mcr-3.1, and qnrS1) underlies local expansion and intercontinental spread in two separate ST34 clones. At the global scale, Southeast Asia was identified as a potential hub for the emergence and dissemination of multidrug resistant Salmonella ST34, and mutation analysis suggests of selection in antimicrobial responses and key virulence factors.

Diterpenoid and phenolic constituents from corn silk (Zea mays) with PTP1B inhibitory activity.

Chemical investigation of corn silk resulted in the isolation of nine secondary metabolites, including a new ent-kaurane diterpenoid, zeamaysditerpene A (1) and eight known compounds, stigmaydene A (2), stigmaydene J (3), stigmaydene L (4), stigmane D (5), demethyltorosaflavone D (6), chrysoeriol 6-C-ß-boivinopyranosyl-7-O-ß-D-glucopyranoside (7), deoxypodophyllotoxin (8), and α-peltatin glucoside (9). Their structures were elucidated using a combination of spectroscopic methods, including 1D and 2D NMR and HRESIQTOF mass spectra. The absolute configuration of 1 was deduced by applying electronic circular dichroism (ECD) calculation method. Among the isolates, only 6 displayed significant inhibition against PTP1B activity in a dose-dependent manner, with an IC50 value of 10.7 ± 0.1 µM. Furthermore, molecular docking simulation was carried out to explore the action perspective of 6 inside the enzyme PTP1B. This finding suggests that 6 might be a potential lead for the development of a new anti-diabetic agent.

Acylated flavonoid glycosides from Barringtonia pendula and their inhibition on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells.

Six new acylated flavonoid glycosides namely barringosides J - O (1-6) along with tephrokaempferoside and barringoside D were isolated from the branches and leaves of Barringtonia pendula. The structural elucidation was confirmed by extensive analysis of their spectroscopic data including HRQTOFMS, 1D and 2D NMR experiments. Moderate inhibitory effects on LPS-induced NO production in RAW264.7 cells were observed for barringosides M (4) and N (5) with IC50 values of 48.40 ± 3.01 and 56.61 ± 3.87 µM, whereas weak inhibition was found for compounds 1-3, 6, and 7 with IC50 values ranging from 64.91 ± 3.68 to 79.80 ± 3.90 µM.

Asterosaponins from the starfish Protoreaster nodosus.

Five asterosaponins (1-5), including one new compound named protonodososide (1), were isolated from the methanol extract of the starfish Protoreaster nodosus, after subjecting to various chromatographic separations. The structural elucidation was confirmed by careful analysis of the 1D, 2D NMR, and HR ESI QTOF mass spectra. The cytotoxicity of isolated compounds was evaluated on five human cancer cell lines including HepG2, KB, MCF7, LNCaP, and SK-Mel2.

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusions: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Isoryanodane diterpene derivatives from Barringtonia macrocarpa.

From the MeOH residue of Barringtonia macrocarpa branches and leaves, one new isoryanodane diterpene, barringisol (1), and two new isoryanodane diterpene glucosides, barringisosides A and B (2 and 3), were obtained using various chromatographic isolations. The structural characterization was confirmed by spectroscopic methods including 1D, 2D NMR and HR-ESI-QTOF-MS. This is the first isolation of isoryanodane diterpene derivatives from Barringtonia species. Moreover, the in vitro cytotoxicity of 1-3 on three human cancer cell lines (HepG2, LNCaP and MCF7) was also accessed using SRB assays.

Models of Aviation Noise Impact in the Context of Operation Decrease at Tan Son Nhat Airport.

Air traffic bans in response to the spread of the coronavirus have changed the sound situation of urban areas around airports. This study aimed to investigate the effect of this unprecedented event on the community response to noise before and after the international flight operation at Tan Son Nhat Airport (TSN) in March 2020. The "before" survey was conducted in August 2019, and the two "after" surveys were conducted in June and September 2020. Structural equation models (SEMs) for noise annoyance and insomnia were developed by linking the questionnaire items of the social surveys. The first effort aimed to achieve a common model of noise annoyance and insomnia, corresponding to the situation before and after the change, respectively. Approximately, 1200 responses were obtained from surveys conducted in 12 residential areas around TSN in 2019 and 2020. The average daily flight numbers observed in August 2019 during the two surveys conducted in 2020 were 728, 413, and 299, respectively. The sound pressure levels of the 12 sites around TSN decreased from 45-81 dB (mean = 64, SD = 9.8) in 2019 to 41-76 dB (mean = 60, SD = 9.8) and 41-73 dB (mean = 59, SD = 9.3) in June and September 2020, respectively. The SEM indicated that the residents' health was related to increased annoyance and insomnia.

High performance of systematic combined urine LAM test and sputum Xpert MTB/RIF® for tuberculosis screening in severely immunosuppressed ambulatory adults with HIV.

BACKGROUND: In people with HIV (PWH), the WHO-recommended tuberculosis four-symptom screen (W4SS) targeting those who need molecular rapid test may be suboptimal. We assessed the performance of different tuberculosis screening approaches in severely immunosuppressed PWH enrolled in the guided-treatment group of the STATIS trial (NCT02057796). METHODS: Ambulatory PWH with no overt evidence of tuberculosis and CD4 cell count <100/µL were screened for tuberculosis prior to antiretroviral therapy (ART) initiation with W4SS, chest X-ray, urine lipoarabinomannan (LAM) test and sputum Xpert MTB/RIF® (Xpert). Correctly and wrongly identified cases by screening approaches were assessed overall and by CD4 count threshold (≤50 and 51-99 cells/µL). RESULTS: Of 525 enrolled participants (median CD4 cell count: 28/µL), 48 (9.9%) were diagnosed with tuberculosis at enrollment. Among participants with a negative W4SS, 16% had either a positive Xpert, a chest X-ray suggestive of tuberculosis or a positive urine LAM test. The combination of sputum Xpert and urine LAM test was associated with the highest proportion of participants correctly identified as tuberculosis (95.8%) and non-tuberculosis cases (95.4%), with proportions equally high among participants with CD4 counts above or below 50 cells/µL. Restricting the use of sputum Xpert, urine LAM test or chest X-ray to participants with a positive W4SS reduced the proportion of wrongly and correctly identified cases. CONCLUSIONS: There is a clear benefit to perform both sputum Xpert and urine LAM tests as tuberculosis screening in all severely immunosuppressed PWH prior to ART initiation, and not only in those with a positive W4SS. CLINICAL TRIALS REGISTRATION: NCT02057796.

Hardware-Based Architecture for DNN Wireless Communication Models.

Multiple Input Multiple Output Orthogonal Frequency Division Multiplexing (MIMO OFDM) is a key technology for wireless communication systems. However, because of the problem of a high peak-to-average power ratio (PAPR), OFDM symbols can be distorted at the MIMO OFDM transmitter. It degrades the signal detection and channel estimation performance at the MIMO OFDM receiver. In this paper, three deep neural network (DNN) models are proposed to solve the problem of non-linear distortions introduced by the power amplifier (PA) of the transmitters and replace the conventional digital signal processing (DSP) modules at the receivers in 2 × 2 MIMO OFDM and 4 × 4 MIMO OFDM systems. Proposed model type I uses the DNN model to de-map the signals at the receiver. Proposed model type II uses the DNN model to learn and filter out the channel noises at the receiver. Proposed model type III uses the DNN model to de-map and detect the signals at the receiver. All three model types attempt to solve the non-linear problem. The robust bit error rate (BER) performances of the proposed receivers are achieved through the software and hardware implementation results. In addition, we have also implemented appropriate hardware architectures for the proposed DNN models using special techniques, such as quantization and pipeline to check the feasibility in practice, which recent studies have not done. Our hardware architectures are successfully designed and implemented on the Virtex 7 vc709 FPGA board.

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).